DK2190502T3 - Combined sensor and infusion set with separate places - Google Patents

Combined sensor and infusion set with separate places Download PDF

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Publication number
DK2190502T3
DK2190502T3 DK08798612.1T DK08798612T DK2190502T3 DK 2190502 T3 DK2190502 T3 DK 2190502T3 DK 08798612 T DK08798612 T DK 08798612T DK 2190502 T3 DK2190502 T3 DK 2190502T3
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Prior art keywords
sensor
apparatus
analyte
layer
patient
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DK08798612.1T
Other languages
Danish (da)
Inventor
Richard Lemos
Antwerp Nannette M Van
Gayane Voskanyan
Ly Phou
Bradley J Enegren
Rajiv Shah
Garry M Steil
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Medtronic Minimed Inc
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Priority to US11/897,106 priority Critical patent/US9968742B2/en
Application filed by Medtronic Minimed Inc filed Critical Medtronic Minimed Inc
Priority to PCT/US2008/074187 priority patent/WO2009032588A1/en
Application granted granted Critical
Publication of DK2190502T3 publication Critical patent/DK2190502T3/en

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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61MDEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M5/00Devices for bringing media into the body in a subcutaneous, intra-vascular or intramuscular way; Accessories therefor, e.g. filling or cleaning devices, arm-rests
    • A61M5/14Infusion devices, e.g. infusing by gravity; Blood infusion; Accessories therefor
    • A61M5/168Means for controlling media flow to the body or for metering media to the body, e.g. drip meters, counters ; Monitoring media flow to the body
    • A61M5/172Means for controlling media flow to the body or for metering media to the body, e.g. drip meters, counters ; Monitoring media flow to the body electrical or electronic
    • A61M5/1723Means for controlling media flow to the body or for metering media to the body, e.g. drip meters, counters ; Monitoring media flow to the body electrical or electronic using feedback of body parameters, e.g. blood-sugar, pressure
    • AHUMAN NECESSITIES
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    • A61BDIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00Detecting, measuring or recording for diagnostic purposes; Identification of persons
    • A61B5/145Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue
    • A61B5/14503Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue invasive, e.g. introduced into the body by a catheter or needle or using implanted sensors
    • AHUMAN NECESSITIES
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    • A61B5/145Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue
    • A61B5/14532Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue for measuring glucose, e.g. by tissue impedance measurement
    • AHUMAN NECESSITIES
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    • A61B5/145Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue
    • A61B5/14546Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue for measuring analytes not otherwise provided for, e.g. ions, cytochromes
    • AHUMAN NECESSITIES
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    • A61BDIAGNOSIS; SURGERY; IDENTIFICATION
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    • A61B5/145Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue
    • A61B5/1468Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue using chemical or electrochemical methods, e.g. by polarographic means
    • A61B5/1473Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue using chemical or electrochemical methods, e.g. by polarographic means invasive, e.g. introduced into the body by a catheter
    • AHUMAN NECESSITIES
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    • A61B5/4839Diagnosis combined with treatment in closed-loop systems or methods combined with drug delivery
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    • A61B5/6847Arrangements of detecting, measuring or recording means, e.g. sensors, in relation to patient specially adapted to be brought in contact with an internal body part, i.e. invasive mounted on an invasive device
    • A61B5/6848Needles
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    • A61B5/68Arrangements of detecting, measuring or recording means, e.g. sensors, in relation to patient
    • A61B5/6846Arrangements of detecting, measuring or recording means, e.g. sensors, in relation to patient specially adapted to be brought in contact with an internal body part, i.e. invasive
    • A61B5/6847Arrangements of detecting, measuring or recording means, e.g. sensors, in relation to patient specially adapted to be brought in contact with an internal body part, i.e. invasive mounted on an invasive device
    • A61B5/6848Needles
    • A61B5/6849Needles in combination with a needle set
    • AHUMAN NECESSITIES
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    • A61MDEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M5/00Devices for bringing media into the body in a subcutaneous, intra-vascular or intramuscular way; Accessories therefor, e.g. filling or cleaning devices, arm-rests
    • A61M5/14Infusion devices, e.g. infusing by gravity; Blood infusion; Accessories therefor
    • A61M5/142Pressure infusion, e.g. using pumps
    • A61M5/14244Pressure infusion, e.g. using pumps adapted to be carried by the patient, e.g. portable on the body
    • A61M5/14248Pressure infusion, e.g. using pumps adapted to be carried by the patient, e.g. portable on the body of the skin patch type
    • AHUMAN NECESSITIES
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    • A61MDEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M5/00Devices for bringing media into the body in a subcutaneous, intra-vascular or intramuscular way; Accessories therefor, e.g. filling or cleaning devices, arm-rests
    • A61M5/14Infusion devices, e.g. infusing by gravity; Blood infusion; Accessories therefor
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    • A61MDEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M5/00Devices for bringing media into the body in a subcutaneous, intra-vascular or intramuscular way; Accessories therefor, e.g. filling or cleaning devices, arm-rests
    • A61M5/14Infusion devices, e.g. infusing by gravity; Blood infusion; Accessories therefor
    • A61M5/168Means for controlling media flow to the body or for metering media to the body, e.g. drip meters, counters ; Monitoring media flow to the body
    • A61M5/172Means for controlling media flow to the body or for metering media to the body, e.g. drip meters, counters ; Monitoring media flow to the body electrical or electronic
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    • A61B5/0002Remote monitoring of patients using telemetry, e.g. transmission of vital signals via a communication network
    • A61B5/0031Implanted circuitry
    • AHUMAN NECESSITIES
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    • A61BDIAGNOSIS; SURGERY; IDENTIFICATION
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    • A61B5/145Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue
    • A61B5/1486Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue using enzyme electrodes, e.g. with immobilised oxidase
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61MDEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M5/00Devices for bringing media into the body in a subcutaneous, intra-vascular or intramuscular way; Accessories therefor, e.g. filling or cleaning devices, arm-rests
    • A61M5/14Infusion devices, e.g. infusing by gravity; Blood infusion; Accessories therefor
    • A61M5/142Pressure infusion, e.g. using pumps
    • A61M5/14244Pressure infusion, e.g. using pumps adapted to be carried by the patient, e.g. portable on the body
    • A61M5/14248Pressure infusion, e.g. using pumps adapted to be carried by the patient, e.g. portable on the body of the skin patch type
    • A61M2005/14252Pressure infusion, e.g. using pumps adapted to be carried by the patient, e.g. portable on the body of the skin patch type with needle insertion means
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61MDEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M5/00Devices for bringing media into the body in a subcutaneous, intra-vascular or intramuscular way; Accessories therefor, e.g. filling or cleaning devices, arm-rests
    • A61M5/14Infusion devices, e.g. infusing by gravity; Blood infusion; Accessories therefor
    • A61M5/158Needles for infusions; Accessories therefor, e.g. for inserting infusion needles, or for holding them on the body
    • A61M2005/1585Needle inserters
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61MDEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M5/00Devices for bringing media into the body in a subcutaneous, intra-vascular or intramuscular way; Accessories therefor, e.g. filling or cleaning devices, arm-rests
    • A61M5/14Infusion devices, e.g. infusing by gravity; Blood infusion; Accessories therefor
    • A61M5/158Needles for infusions; Accessories therefor, e.g. for inserting infusion needles, or for holding them on the body
    • A61M2005/1586Holding accessories for holding infusion needles on the body
    • AHUMAN NECESSITIES
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    • A61MDEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M5/00Devices for bringing media into the body in a subcutaneous, intra-vascular or intramuscular way; Accessories therefor, e.g. filling or cleaning devices, arm-rests
    • A61M5/14Infusion devices, e.g. infusing by gravity; Blood infusion; Accessories therefor
    • A61M5/158Needles for infusions; Accessories therefor, e.g. for inserting infusion needles, or for holding them on the body
    • A61M2005/1587Needles for infusions; Accessories therefor, e.g. for inserting infusion needles, or for holding them on the body suitable for being connected to an infusion line after insertion into a patient
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61MDEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M5/00Devices for bringing media into the body in a subcutaneous, intra-vascular or intramuscular way; Accessories therefor, e.g. filling or cleaning devices, arm-rests
    • A61M5/14Infusion devices, e.g. infusing by gravity; Blood infusion; Accessories therefor
    • A61M5/168Means for controlling media flow to the body or for metering media to the body, e.g. drip meters, counters ; Monitoring media flow to the body
    • A61M5/172Means for controlling media flow to the body or for metering media to the body, e.g. drip meters, counters ; Monitoring media flow to the body electrical or electronic
    • A61M5/1723Means for controlling media flow to the body or for metering media to the body, e.g. drip meters, counters ; Monitoring media flow to the body electrical or electronic using feedback of body parameters, e.g. blood-sugar, pressure
    • A61M2005/1726Means for controlling media flow to the body or for metering media to the body, e.g. drip meters, counters ; Monitoring media flow to the body electrical or electronic using feedback of body parameters, e.g. blood-sugar, pressure the body parameters being measured at, or proximate to, the infusion site
    • AHUMAN NECESSITIES
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    • A61M2230/00Measuring parameters of the user
    • A61M2230/20Blood composition characteristics
    • A61M2230/201Glucose concentration

Description

Description

Background of the Invention 1. Field of the Invention.

[0001] Embodiments of the invention relate to apparatuses that combine sensor and infusion elements. 2. Description of Related Art.

[0002] Insulin must be provided to people with Type 1 and many with Type 2 diabetes. Traditionally, since it cannot be taken orally, insulin has been injected with a syringe. More recently, use of external infusion pump therapy has been increasing, especially for delivering insulin for diabetics using devices worn on a belt, in a pocket, or the like, with the insulin delivered via a catheter with a percutaneous needle or cannula placed in the subcutaneous tissue. For example, as of 1995, less than 5% of Type 1 diabetics in the United States were using pump therapy. There are now about 12% of the currently over 1,000,000 Type 1 diabetics in the U.S. using insulin pump therapy, and the percentage is now growing at an absolute rate of over 2% each year. Moreover, the number of Type 1 diabetics is growing at 3% or more per year. In addition, growing numbers of insulin using Type 2 diabetics are also using external insulin infusion pumps. Physicians have recognized that continuous infusion provides greater control of a diabetic's condition, and are also increasingly prescribing it for patients. In addition, medication pump therapy is becoming more important for the treatment and control of other medical conditions, such as pulmonary hypertension, HIV and cancer.

[0003] Pump therapy systems have been developed that deliver medication by infusion into subcutaneous tissue using an infusion set with needles and/or a soft cannula. The soft cannula of the infusion set is normally inserted into the skin with a needle to prevent kinking of the soft cannula. Automatic insertion devices have been utilized to reduce the discomfort and pain involved with the insertion of infusion sets.

[0004] In addition to delivering medication to a patient, a number of other medical devices have been designed to determine body characteristics by obtaining a sample of bodily fluid. A variety of implantable electrochemical sensors have been developed for detecting and/ or quantifying specific agents or compositions in a patient's blood. For instance, glucose sensors have been developed for use in obtaining an indication of blood glucose levels in a diabetic patient. Such readings can be especially useful in monitoring and/or adjusting a treatment regimen that typically includes the regular administration of insulin to the patient. Thus, blood glucose readings are particularly useful in improving medical therapies with semi-automated medication infusion pumps of the external type, as generally described in U.S. Pat. Nos. 4,562,751; 4,678,408; and 4,685,903; or automated implantable medication infusion pumps, as generally described in U.S. Pat. No. 4,573,994.

[0005] Document US 2006/0253085, on which the pre-characterizing part of claim 1 is based, shows a dual insertion set, which allows for the insertion of both a cannula and a sensor. Piercing members help insert the cannula or sensor and are then withdrawn.

Summary of the Invention [0006] In its broadest form the invention is as set out in claim 1 below. Embodiments of the invention disclosed herein include apparatuses that combine sensor elements with elements designed to infuse a fluid to a patient in a manner that optimizes a number of sensor characteristics including for example specificity. An illustrative embodiment of the invention is an apparatus for supplying a fluid to a body of a patient (e.g. insulin) and for monitoring a body characteristic of the patient (e.g. blood glucose). The apparatus typically comprises a base adapted to secure the apparatus to the skin of a patient, a first piercing member coupled to and extending from the base and operatively coupled to at least one cannula for infusing a fluid to an infusion site as well as a second piercing member coupled to and extending from the base and operatively coupled to an electrochemical sensor having a sensor electrode for determining at least one body characteristic of the patient at a sensor placement site. In such embodiments of the invention, the first and second piercing members are coupled to the base in an orientation such that when the first and second piercing members can be operatively coupled to the base and inserted into a patient, a first perforation channel made by the first piercing member is not in operable contact with a second perforation channel made by the second piercing member. This embodiment can be used for example to avoid interference of an electrochemical sensor that monitors a body characteristic of a patient, where the interference is caused by a interferant present in an infusate (e.g. a phenolic preservative). In particular, by using an insertable apparatus where a first perforation channel made by the first piercing member is not in operable contact with a second perforation channel made by the second piercing member, a fluid infused to the infusion site (which may contain an interfering species) is prevented from flowing through a perforation channel to the sensor.

[0007] In typical embodiments of the invention, the sensor elements and infusion elements (including and their associated piercing members) are positioned on the apparatus in a configuration designed to optimize sensor function. In some embodiments of the invention for example, the first piercing member on the apparatus is shorter than the second piercing member. In certain embodiments of the invention, the first and second piercing members (e.g. metallic needles) are coupled to the base in orientations designed to dispose the infusion site where the fluid exits the cannula in one in vivo environment and the sensor that senses a physiological characteristic in another in vivo environment. In a typical embodiment of the invention, the first and second piercing members are coupled to the base in an orientation such that when the first and second piercing members are inserted into a patient, the infusion site is disposed within a layer of the epidermis and the sensor electrode is disposed within a layer of the dermis. In related embodiments of the invention, the first and second piercing members are coupled to the base in orientations designed to dispose the in fusion site where the fluid exits the cannula at a first in vivo location that is placed a certain distance from the in vivo location in which the sensor is disposed. For example, in an illustrative embodiment of the invention, the first and second piercing members are coupled to the base in an orientation such that when the first and second piercing members are inserted into a patient, the infusion site and the sensor electrode are separated by at least 7 millimeters of tissue. By using an insertable apparatus where the infusion site and the sensor are separated by at least 7 millimeters of tissue, a fluid infused to the infusion site (which may contain an interfering species) is absorbed by the surrounding tissue before it can diffuse to the reactive surface of the sensor. In yet another embodiment of the invention, the first and second piercing members are coupled to the base in an orientation so that when the cannula and the sensor electrode are disposed in a patient, the cannula and the sensor electrode anchor the apparatus to the skin of the patient, thereby stabilizing sensor readings, for example by inhibiting movement of sensor in the environment in which it is sensing an analyte.

[0008] In certain embodiments of the invention, the apparatus can have a modular design that allows the cannula and/or the sensor to be replaced independently of other components of the apparatus. For example, the apparatuses disclosed herein iinclude embodiments where the first and second piercing members are disposed on a hub that can operatively engage and disengage from the base. In some embodiments of the invention having a hub, the hub comprises a finger grip member that allows the hub to be gripped as it is disengaged from the base. In some embodiments of the invention, the apparatus can include an array of microneedles for infusing a fluid to an infusion site. Certain embodiments of the invention can include additional elements, for example infusion set tubing adapted to connect to the cannula. Embodiments of the invention can further comprise additional elements designed to facilitate the delivery of a therapeutic composition, for example a medication infusion pump adapted to connect to infusion set tubing.

[0009] Certain embodiments of the invention are designed for use with specific electrochemical sensor designs. For example in some embodiments of the invention, the sensor portion of the apparatus comprises a plurality of layers, wherein at least one of the layers comprises a base substrate on which the electrode is disposed, the base substrate including a geometric feature selected to increase the surface area of an electrochemically reactive surface on the electrode disposed thereon such that surface area to volume ratio of the electrochemically reactive surface area of the electrode disposed on the geometric feature is greater than surface area-to-volume ratio of the reactive surface of the electrode when disposed on a flat surface, or an analyte sensing layer that detectably alters the electrical current at the electrode in the presence of an analyte, or an adhesion promoting layer that promotes the adhesion between one or more layers of the sensor, or an analyte modulating layer that modulates the diffusion of a analyte therethrough; or a cover layer that is impermeable to blood glucose, wherein the cover layer includes an aperture.

[0010] Also envisaged are articles of manufacture such as dual insertion sets including a base, a cannula, piercing member and/or sensor elements, and kits. A kit having an apparatus designed to both infuse a fluid into a patient as well as sensing an analyte as is described above, is provided. The kit and/or sensor set typically comprises a container, a label and an apparatus as described above. The typical kit comprising a container and, within the container, an apparatus having a design as disclosed herein and instructions for using the apparatus.

[0011] Other objects, features and advantages of the present invention will become apparent to those skilled in the art from the following detailed description. It is to be understood, however, that the detailed description and specific examples, while indicating some embodiments of the present invention are given by way of illustration and not limitation. Many changes and modifications within the scope of the present invention may be made without departing from the spirit thereof, and the invention includes all such modifications.

Brief Description of the Figures [0012] FIG. 1 provides a schematic of the well known reaction between glucose and glucose oxidase. As shown in a stepwise manner, this reaction involves glucose oxidase (GOx), glucose and oxygen in water. In the reductive half of the reaction, two protons and electrons are transferred from β-D-glucose to the enzyme yielding d-gluconolactone. In the oxidative half of the reaction, the enzyme is oxidized by molecular oxygen yielding hydrogen peroxide. The d-gluconolactone then reacts with water to hydrolyze the lactone ring and produce gluconic acid. In certain electrochemical sensors of the invention, the hydrogen peroxide produced by this reaction is oxidized at the working electrode (H202 —»· 2H+ + 02 + 2e'). FIG. 2 provides a diagrammatic view of a typical configuration of the sensor element constituents. FIG. 3 provides a diagrammatic side view of a dual insertion set where a sensor and a cannula are placed at different depths in the body of a patient. FIGS. 4A-4E provide a diagrammatic view of an embodiment of the invention. In this embodiment, the sensor and sensor connector are built toward one edge of the assembly, while the cannula is positioned toward the center, both are at a 90° angle to the skin surface (FIG. 4A). For insertion, a hub with two needles attached is engagable with the assembly (FIG. 4B). The set is then inserted into the subcutaneous tissue, either manually or with an automatic insertion device. The hub with needles is then removed and discarded. The infusion catheter can then be the attached and the sensor is plugged into a cable or transmitter (FIG. 4C and 4D). Alternative embodiments can include for example variations where two or more infusion cannulae can be used to further reduce any interference or localized tissue effects (FIG. 4E).

Detailed Description of the Embodiments [0013] Unless otherwise defined, all terms of art, notations and other scientific terms or terminology used herein are intended to have the meanings commonly understood by those of skill in the art to which this invention pertains. In some cases, terms with commonly understood meanings are defined herein for clarity and/or for ready reference, and the inclusion of such definitions herein should not necessarily be construed to represent a substantial difference over what is generally understood in the art. Many of the techniques and procedures described or referenced herein are well understood and commonly employed using conventional methodology by those skilled in the art. As appropriate, procedures involving the use of commercially available kits and reagents are generally carried out in accordance with manufacturer defined protocols and/or parameters unless otherwise noted. A number of terms are defined below.

[0014] The term "analyte" as used herein is a broad term and is used in its ordinary sense, including, without limitation, to refer to a substance or chemical constituent in a fluid such as a biological fluid (for example, blood, interstitial fluid, cerebral spinal fluid, lymph fluid or urine) that can be analyzed. Analytes can include naturally occurring substances, artificial substances, metabolites, and/or reaction products. In some embodiments, the analyte for measurement by the sensing regions, devices, and methods is glucose. However, other analytes are contemplated as well, including but not limited to, lactate. Salts, sugars, proteins fats, vitamins and hormones naturally occurring in blood or interstitial fluids can constitute analytes in certain embodiments. The analyte can be naturally present in the biological fluid or endogenous; for example, a metabolic product, a hormone, an antigen, an antibody, and the like. Alternatively, the analyte can be introduced into the body or exogenous, for example, a contrast agent for imaging, a radioisotope, a chemical agent, a fluorocarbon-based synthetic blood, or a drug or pharmaceutical composition, including but not limited to insulin. The metabolic products of drugs and pharmaceutical compositions are also contemplated analytes.

[0015] The term "sensor," as used herein, is a broad term and is used in its ordinary sense, including, without limitation, the portion or portions of an analytemonitoring device that detects an analyte. In one embodiment, the sensor includes an electrochemical cell that has a working electrode, a reference elec- trode, and optionally a counter electrode passing through and secured within the sensor body forming an electrochemically reactive surface at one location on the body, an electronic connection at another location on the body, and a membrane system affixed to the body and covering the electrochemically reactive surface. During general operation of the sensor, a biological sample (for example, blood or interstitial fluid), or a portion thereof, contacts (directly or after passage through one or more membranes or domains) an enzyme (for example, glucose oxidase); the reaction of the biological sample (or portion thereof) results in the formation of reaction products that allow a determination of the analyte level in the biological sample.

[0016] The term "electrochemical cell," as used herein, is a broad term and is used in its ordinary sense, including, without limitation, a device in which chemical energy is converted to electrical energy. Such a cell typically consists of two or more electrodes held apart from each other and in contact with an electrolyte solution. Connection of the electrodes to a source of direct electric current renders one of them negatively charged and the other positively charged. Positive ions in the electrolyte migrate to the negative electrode (cathode) and there combine with one or more electrons, losing part or all of their charge and becoming new ions having lower charge or neutral atoms or molecules; at the same time, negative ions migrate to the positive electrode (anode) and transfer one or more electrons to it, also becoming new ions or neutral particles. The overall effect of the two processes is the transfer of electrons from the negative ions to the positive ions, a chemical reaction.

[0017] The terms "electrochemically reactive surface" and "electroactive surface" as used herein are broad terms and are used in their ordinary sense, including, without limitation, the surface of an electrode where an electrochemical reaction takes place. In one example, a working electrode measures hydrogen peroxide produced by the enzyme catalyzed reaction of the analyte being detected reacts creating an electric current (for example, detection of glucose analyte utilizing glucose oxidase produces H202 as a by product, H202 reacts with the surface of the working electrode producing two protons (2H+), two electrons (2e‘) and one molecule of oxygen (02) which produces the electronic current being detected). In the case of the counter electrode, a reducible species, for example, 02 is reduced at the electrode surface in order to balance the current being generated by the working electrode.

[0018] The term "sensing region" as used herein is a broad term and is used in its ordinary sense, including, without limitation, the region of a monitoring device responsible for the detection of a particular analyte. In an illustrative embodiment, the sensing region can comprise a non-conductive body, a working electrode, a reference electrode, and a counter electrode passing through and secured within the body forming electrochemically reactive surfaces on the body and an electronic connective means at another location on the body, and a one or more layers covering the electrochemically reactive surface.

[0019] The terms "electrical potential" and "potential" as used herein, are broad terms and are used in their ordinary sense, including, without limitation, the electrical potential difference between two points in a circuit which is the cause of the flow of a current. The term "system noise," as used herein is a broad term and is used in its ordinary sense, including, without limitation, unwanted electronic or diffusion-related noise which can include Gaussian, motion-related, flicker, kinetic, or other white noise, for example.

[0020] The terms "interferants" and "interfering species," as used herein, are broad terms and are used in their ordinary sense, including, but not limited to, effects and/or species that interfere with the measurement of an analyte of interest in a sensor to produce a signal that does not accurately represent the analyte measurement. Typically, an "interferant" or "interfering species" is an electroactive compound other than the analyte of interest which, when present in an ionically conductive material, generates a response unrelated to the concentration (or amount) of analyte being measured by the sampling system, thus interfering with the detection of an analyte in the material. In electrochemical sensors, interfering species can be for example compounds with an oxidation potential that overlaps with the analyte to be measured.

[0021] The term "phenolic preservative" as used herein refers to art accepted phenolic preservatives that can be used in therapeutic compositions such as chlorocresol, m-cresol, phenol, or mixtures thereof.

[0022] As discussed in detail below, embodiments of the invention provide apparatuses that include sensor elements of the type used, for example, in subcutaneous or transcutaneous monitoring of blood glucose levels in a diabetic patient. These apparatuses further include infusion elements such as cannulae of the type used, for example, to infuse insulin into a diabetic patient. In particular embodiments, the invention provides a system for regulating the rate of insulin infusion into the body of a patient based on a glucose concentration measurement taken from the body. In such embodiments, the elements are organized to be spatially separated and further designed to be inserted into proximal yet separate in vivo environments. This organization provides a number of unexpected benefits and for example functions to inhibit sensor interference caused by various compounds present within therapeutic compositions being infused into the body via the infusion elements. Embodiments of the invention may be employed in various infusion environments including, but not limited to biological implant environments. Other environments include, but are not limited to external infusion devices, pumps, or the like.

[0023] Embodiments of the invention can include an electrochemical sensor that measures a concentration of an analyte of interest or a substance indicative of the concentration or presence of the analyte in fluid. In some embodiments, the sensor is a continuous device, for example a subcutaneous, transdermal, or intravascular device. The sensor embodiments disclosed herein can use any known method, including invasive, minimally invasive, and non-invasive sensing techniques, to provide an output signal indicative of the concentration of the analyte of interest. Typically, the sensor is of the type that senses a product or reactant of an enzymatic reaction between an analyte and an enzyme in the presence of oxygen as a measure of the analyte in vivo or in vitro. Such sensors typically comprise a plurality of layers as discussed in detail below. In typical embodiments, the sensor can use an amperometric, coulometric, conductimet-ric, and/or potentiometric technique for measuring the analyte.

[0024] Embodiments of the invention include an apparatus having a constellation of elements including a sensor element as well as an infusion element so as to provide a dual insertion set, i.e. an apparatus having a base that is operatively coupled to both infusion delivery elements and physiological characteristic sensor elements. In some embodiments, the infusion element of the dual insertion set infuses a fluid, such as a fluid that contains medications, chemicals, enzymes, antigens, hormones, vitamins or the like, into a body of a patient. In particular embodiments of the invention, the dual insertion set may be coupled to an external infusion device, which includes an RF programming capability, a carbohydrate (or bolus) estimation capability and/or vibration alarm capability, as described in U.S. Pat. No. 6,554,798 entitled "External Infusion Device with Remote Programming, Bolus Estimator and/or Vibration Alarm Capabilities". In other embodiments, the dual insertion set may be coupled to other infusion pumps such as the Animas IR-1250, the Deltec Cozmo®, the Disetronic D-Tron® plus, the MiniMed Paradigm®515/715, and the Dana Diabecare® coupled to an external infusion device, the dual insertion set may also include a disconnect cable, allowing the patient to easily disconnect the dual insertion set from the external infusion device to go swimming, take a shower or the like, without having to entirely remove the dual insertion set from the body of the patient. Particular embodiments are directed towards use in humans; however, in alternative embodiments, the dual insertion set may be used in animals.

[0025] In certain embodiments, the dual insertion set may be adapted to fit in an insertion tool, as described in U.S. Pat. No. 5,851,197 entitled "Injector For A Subcutaneous Infusion Set," U.S. Pat. No. 6,093,172 entitled "Injector For A Subcutaneous Insertion Set," and U.S. Pat. No. 6,607,509 entitled "Insertion Device For An Insertion Set And Method Of Using The Same," The dual insertion may be further adapted for low profile and unobtrusive placement on the patient. In other embodiments, the shape of the dual insertion set may be rectangular, circular, square or the like.

[0026] A sensor included in the dual insertion set may be implanted in and/or through subcutaneous, dermal, sub-dermal, inter-peritoneal or peritoneal tissue. In some embodiments of the invention, the sensor may be coupled to a monitor for determining glucose levels in the blood and/or body fluids of the patient without the use of, or necessity of, a wire or cable connection between the transmitter and the monitor. In these embodiments, the sensor utilizes glucose oxidase to determine glucose levels. In still further embodiments, the sensor may use other materials such as optical, fluorescence or electrical materials to determine glucose levels. It will be recognized that further embodiments of the invention may be used to determine the levels of other agents, characteristics or compositions, such as hormones, cholesterol, medication concentrations, pH, oxygen saturation, viral loads (e.g., HIV), or the like. In other embodiments, the sensor may also include the capability to be programmed or calibrated using data received by a telemetered characteristic monitor transmitter device, or may be calibrated at the monitor device (or receiver), as described in U.S. Pat. No. 6,809,653 entitled "Telemetered Characteristic Monitor System And Method Of Using The Same," The telemetered characteristic monitor system may be primarily adapted for use in subcutaneous human tissue. However, still further embodiments may be placed in other types of tissue, such as muscle, lymph, organ tissue, veins, arteries or the like, and used in animal tissue. Embodiments may provide sensor readings on an intermittent, near-continuous and/or continuous basis.

[0027] In some embodiments of the invention, the apparatuses of the invention may be coated with medications or other agents that inhibit infection and/or promote healing of the insertion site, as described in U.S. Pat. No. 5,505,713 entitled "Indwelling Catheter With A Stable Enzyme Coating," U.S. Pat. No. 6,475,196 entitled "Subcutaneous Infusion Cannula," U.S. Pat. No. 6,770,729 entitled "Polymer Compositions containing Bioactive Agents and Methods for Their Use," and U.S. Patent Application Publication No. 20030199837 entitled "Anti-Inflammatory Biosensor For Reduced Biofouling And Enhanced Sensor Performance" herein. Particular embodiments of the dual insertion set are for transcutaneous placement of the dual insertion set in subcutaneous tissue. In still further embodiments, the sensor portion and infusion portion of the dual insertion may be placed at different depths within the body of the patient.

[0028] The dual insertion set of the invention may be used to monitor body characteristics of the patient In one embodiment, the sensor portion of the dual insertion set monitors blood glucose levels and can be used in conjunction with automated and/or semi-automated medication infusion pumps. In additional embodiments, the sensor portion may be used to determine the levels of other agents, characteristics or compositions, such as hormones, cholesterol, medication concentrations, pH, oxygen saturation, viral loads (e.g., HIV), or the like. The infusion portion of the dual insertion set may be used to provide fluids to the body of a patient. In one embodiment, the infusion portion provides insulin to a diabetic patient. In other embodiments, the infusion portion provides medication, chemicals, enzymes, antigens, hormones, vitamins or the like, to the body of the patient.

[0029] As discussed below, embodiments of the invention disclosed herein include sensor and infusion elements and arrangements or configurations of these elements selected to produce optimized sensing properties. The disclosure further provides methods for making and using apparatuses having this combination of elements. While some embodiments of the invention pertain to glucose and/or lactate sensors, a variety of the elements disclosed herein (e.g. piercing members having an architectural organization that functions to inhibit an infused fluid from contacting an implanted sensor) can be adapted for use with any one of the wide variety of sensors known in the art. The analyte sensor elements, architectures and methods for making and using these elements that are disclosed herein can be used to establish a variety of layered sensor structures. Such combined sensor and infusion device elements of the invention exhibit a surprising degree of flexibility and versatility, characteristics which allows these embodiments to be adapted and implemented with a wide variety of known infusion and sensor sets, including for example those described in U.S. Patent Application No. 20050115832, U.S. Pat. Nos. 6,001,067, 6,702,857, 6,212,416, 6,119,028, 6,400,974, 6,595,919, 6,141,573, 6,122,536, 6,512,939 5,605,152, 4,431,004, 4,703,756, 6,514,718, 5,985,129, 5,390,691,5,391,250, 5,482,473, 5,299,571, 5,568,806, 5,494,562, 6,120,676, 6,542,765 as well as PCT International Publication Numbers WO 01/58348, WO 04/021877, WO 03/034902, WO 03/035117, WO 03/035891, WO 03/023388, WO 03/022128, WO 03/022352, WO 03/023708, WO 03/036255, W003/036310 and WO 03/074107, and European Patent Application EP 1153571.

[0030] Specific aspects of the invention are discussed in detail in the following sections.

I. TYPICAL ELEMENTS, CONFIGURATIONS AND ANALYTE

SENSORS THAT CAN BE USED WITH EMBODIMENTS OF THE INVENTION

[0031] Currently, when an insulin pump wearer wants to use a subcutaneous glucose sensor, they typically insert and wear two separate disposable sets, one for the sensor and one for the infusion catheter. Embodiments of the apparatus design described herein allows the sensor and infusion catheter to be built into a single set, which greatly improves comfort and convenience for the patient. For example, a combination glucose sensor/insulin infusion reduces both the amount of hardware the patient has to wear on their body and the number of needle sticks required for use. In certain arrangements the 3-D architectural configuration of the elements on the apparatus are arranged so that the relative in vivo positioning of the infusion catheter and the sensor in a patient are precisely controlled so as to inhibit the ability of a liquid infused by the cannula (e.g. a therapeutic insulin composition comprising a phenolic preservative) to flow from the site of infusion to the sensor.

A. OPTIMIZED CONFIGURATIONS

[0032] As shown in the drawings for example, arrangements disclosed herein are embodied in an apparatus (typically a dual insertion set) that functions to both supply fluids to the body of patient (e.g. insulin) as well as to monitor body characteristics of that patient (e.g. blood glucose levels). The apparatus embodying the invention has two piercing members, to pierce the skin during insertion. The piercing member(s) may be a metal needle, hollow, solid, half needle (or other fraction) or the like having a diameter in the range of 18 gauge - 29 gauge, or the like, or any range there between. In related embodiments, the piercing member(s) may be made out of other materials, such as ceramic, plastic, composites, silicon micro-needles, biodegradable, hydrophilic substances, substances that soften and/or change once in contact with the body and/or bodily fluids, or the like. In other embodiments, the apparatus may include at least three or more piercing members. In still further embodiments, the piercing member can include and/or be replaced by replace a cannula that remain in the body to deliver fluids. Other embodiments include at least two or more piercing members. The at least piercing member(s) are coupled to and extends from the base so as to facilitate insertion of the at least one cannula and/or the at least one sensor.

[0033] Embodiments of the invention disclosed herein include apparatuses that combine elements designed to infuse a fluid to a patient with electrochemical analyte sensor elements in a manner that optimizes a number of sensor characteristics including the specificity of the analyte sensors. An illustrative embodiment of the invention is an apparatus for supplying a fluid to a body of a patient (e.g. insulin) and for monitoring a body characteristic of the patient (e.g. blood glucose), the apparatus comprising a base adapted to secure the apparatus to the skin of a patient, a first piercing member coupled to and extending from the base, wherein the first piercing member is operatively coupled to at least one cannula for infusing a fluid to an infusion site, a second piercing member coupled to and extending from the base and operatively coupled to an electrochemical sensor having a sensor electrode for determining at least one body characteristic of the patient at a sensor placement site. In this embodiment of the invention, the first and second piercing members are coupled to the base in an orientation such that when the first and second piercing members are operatively coupled to the base and inserted into a patient, a first perforation channel (i.e. an in vivo channel created by the piercing member as it is inserted into a tissue) made by the first piercing member is not in operable contact with a second perforation channel made by the second piercing member. By using an apparatus having elements disposed in this type of orientation, when the device is inserted into the body, the perforation channels created by the infusion element(s) and the perforation channel created by the sensor element(s) are separate and not in contact, a structure that thereby avoids the possibility of a fluid infused from the infusion element(s), one which may contain an interfering species, from travelling through perforation channels to access and possibly interfere with the sensor element.

[0034] In certain embodiments of the invention, the first and second piercing members (e.g. metallic needles) are coupled to the base in orientations designed to dispose the infusion site where the fluid exits the cannula in one in vivo environment and the sensor in another in vivo environment. For example, in one embodiment of the invention, the first and second piercing members are coupled to the base in an orientation such that when the first and second piercing members are inserted into a patient, the infusion site is disposed within a layer of the epidermis and the sensor electrode is disposed within a layer of the dermis. In related embodiments of the invention, the first and second piercing members are coupled to the base in orientations designed to dispose the infusion site where the fluid exits the cannula at a first in vivo location that is placed a certain distance from the in vivo location in which the sensor is disposed. This distance is selected to be that where the infusion site and the sensor site are far enough apart so that a fluid infused at an infusion site is absorbed by the surrounding tissue before it can access the sensor element. In this context, studies show that in certain embodiments of the invention, a distance of 7 millimeters is a sufficient distance to allow a fluid infused at an infusion site to be absorbed by the surrounding tissue before it can access the sensor element.

[0035] The optimal distance between the infusion site and the sensor element may vary for example depending upon where the apparatus is to be placed. The distance between the infusion site and the sensor element that is sufficient to avoid or inhibit sensor interference caused by the presence of an interfering species in an infused composition in each specific situation can be tested using the illustrative methods and apparatuses disclosed herein. Illustrative tests show that a separation of 7 millimeters of tissue is sufficient under typical conditions used to infuse therapeutic compositions. For example, an approximately 200 μΙ volume of fluid containing an interfering compound can be infused over a period of approximately 5-15 minutes at a site that is separated by 7 millimeters of tissue from the electrode of an electrochemical sensor without sensor function being compromised by contact with an interferent. The exact distance may be altered depending upon factors including the amount of fluid infused, the rate of infusion (e.g. a slower infusion rate will allow the infused composition to be absorbed at the site and not contact a proximal sensor) and the tissue into which the composition is infused. In this context, some embodiments of the invention, the first and second piercing members are coupled to the base in an orientation such that when the first and second piercing members are inserted into a patient, the infusion site and the sensor electrode are separated by at least 4, 5, 6 or 7, 8 or 9 millimeters of tissue. In yet another embodiment of the invention, the first and second piercing members are coupled to the base in an orientation so that when the cannula and the sensor electrode are disposed in a patient, the cannula and the sensor electrode anchor the apparatus to the skin of the patient, thereby stabilizing sensor readings, for example by inhibiting movement of sensor in the environment in which it is sensing an analyte. In particular, by disposing the infusion catheter and the sensor electrode in the tissue relative to each other in a manner results in the apparatus being secured to the skin, this anchoring configuration functions to inhibit movement of sensor in the environment in which it is sensing an analyte, thereby stabilizing the sensor readings by repeatedly obtaining a sample to be tested from the same in vivo environment from which the previous sample was obtained (and not an environment which has shifted due to sensor movement).

[0036] Certain embodiments of the invention include methods which use an apparatus designed to exhibit multiple effects. For example, one such embodiment of the invention is a method for inhibiting interference of an electrochemical sensor that monitors a body characteristic of a patient, wherein the interference is caused by a interferant present in an infusate infused by an apparatus for supplying a fluid to a body of a patient. The method comprises supplying a fluid to a body of a patient using an apparatus comprising a base adapted to secure the apparatus to the skin of a patient, a first piercing member coupled to and extending from the base, wherein the first piercing member comprises at least one cannula for infusing a fluid to an infusion site, a second piercing member coupled to and extending from the base and including the electrochemical sensor having a sensor electrode for determining at least one body characteristic of the patient at a sensor placement site. In this embodiment of the invention interference is inhibited by using an apparatus having a organization of elements selected so that the first and second piercing members are coupled to the base in an orientation such that; (1) when the first and second piercing members are inserted into a patient, a first perforation channel made by the first piercing member is not in operable contact with a second perforation channel made by the second piercing member such that a fluid infused to the infusion site cannot flow through the first perforation channel or the second perforation channel to the sensor; (2) the infusion site is disposed within a layer of the epidermis and the sensor electrode is disposed within a layer of the dermis; and (3) the infusion site and the sensor electrode are separated by at least, 4, 5, 6 or 7 millimeters of tissue. Optionally such methods include those where the first and second piercing members are coupled to the base in an orientation so that when the cannula and the sensor electrode are disposed in a patient, the cannula and the sensor electrode anchor the apparatus to the skin of the patient, thereby stabilizing sensor readings.

[0037] In some embodiments of the invention, the apparatus is in a modular configuration that allows the cannula and the sensor to be replaced independently of other components of the apparatus. In addition, the apparatuses disclosed herein include embodiments where the first and second piercing members are disposed on a hub that can operatively engage and disengage from the base. In certain embodiments of the invention having a hub, the hub comprises a finger grip member that allows the hub to be gripped as it is disengaged from the base. In some embodiments of the invention, the first piercing member on the apparatus is shorter than the second piercing member. In certain embodiments of the invention, the apparatus includes an array of microneedles for infusing a fluid to an infusion site. Certain embodiments of the invention include additional element, for example infusion set tubing adapted to connect to the cannula. Other embodiments of the invention can further comprise a medication infusion pump adapted to connect to the infusion set tubing.

[0038] Certain embodiments of the invention are designed for use with certain sensor configurations. For example, interference believed to be caused by phenolic preservatives present in therapeutic insulin compositions is observed in the electrochemical sensors discussed in detail herein. Consequently, in some embodiments of the invention, the sensor portion of the apparatus comprises a plurality of layers, wherein at least one of the layers comprises a base substrate on which the electrode is disposed, the base substrate including a geometric feature selected to increase the surface area of an electrochemically reactive surface on the electrode disposed thereon such that surface area to volume ratio of the electrochemically reactive surface area of the electrode disposed on the geometric feature is greater than surface area-to-volume ratio of the reactive surface of the electrode when disposed on a flat surface, or an analyte sensing layer that detectably alters the electrical current at the electrode in the presence of an analyte, or an adhesion promoting layer that promotes the adhesion between one or more layers of the sensor, or an analyte modulating layer that modulates the diffusion of a analyte therethrough; or a cover layer that is impermeable to blood glucose, wherein the cover layer includes an aperture. While certain embodiments of the invention are directed to avoiding or inhibiting interference believed to be caused by phenolic preservatives present in therapeutic insulin compositions is observed in the electrochemical sensors discussed in detail herein, the apparatuses and methods disclosed herein can be used to avoid interference observed in a variety of sensors and caused by a wide variety of compounds.

[0039] One embodiment of the invention is a dual insertion set for supplying a fluid to a body of a patient and for monitoring a body characteristic of the patient which includes a base, an infusion portion, a sensor portion and at least two piercing members. The base is used to secure the dual insertion set to the skin of a patient. The infusion portion includes at least one cannula for supplying a fluid to an infusion placement site, which is coupled to and extends from the base. The at least one cannula has at least one lumen with a distal end for fluid communication with the placement site and at least one port structure formed near another end of the at least one lumen opposite the distal end. The sensor portion includes at least one sensor having at least one sensor electrode formed on a substrate. The at least one sensor is for determining at least one body characteristic of the patient at a sensor placement site. The piercing members are coupled to and extends from the base to facilitate insertion of the at least one cannula and the at least one sensor. The at least one cannula may also include at least one opening for infusing the fluid into the body of the patient. The structure, geometry and orientation of the piercing members on the apparatuses of the invention can be precisely controlled so that a liquid infused by the cannula of the apparatus will be absorbed by the body and not flow from the site of infusion to the sensor of the apparatus. In some embodiments, the piercing member is a metal needle and the infused fluid is insulin. In other embodiments, the at least one monitored body characteristic is blood glucose. Additional embodiments may include an internal power supply for the at least one sensor. In further embodiments, the internal power supply may drive a leak detection system.

[0040] Referring now to the figures, as illustrated in FIG. 3, an apparatus comprising a dual insertion set 10 includes a sensor portion 20, an infusion portion 30, a base 40, a sensor 22, a cannula 33, and piercing members 24 and 34. Both portions 20 and 30 of the dual insertion set 10 are secured to base 40. Infusion portion 30 is connected at one end to tubing 50 that is connected to an external infusion device, pump or the like. The sensor portion 20 is particularly designed for facilitating accurate placement of a sensor, i.e., a flexible thin film electrochemical sensor of the type used for monitoring specific blood parameters representative of a patient condition, as described in U.S. Pat. No. 5,391,250 entitled "Method of Fabricating Thin Film Sensors" and U.S. Pat. No. 6,484,046 entitled "Electrochemical Analyte Sensor". In some embodiments, the sensor portion 20 is used to monitor blood glucose levels in diabetic patients as described in U.S. Pat. Nos. 5,390,671, 5,568,806 and 5,586,553, entitled "Transcutaneous Sensor Insertion Set".

[0041] As illustrated by the figures, embodiments of the apparatuses disclosed herein can be adapted for use with a variety of elements. Embodiments shown in FIG. 4 for example include elements such as a base or housing 100, elements comprising a combination of a sensor and insertion needle 120 or a cannula and insertion needle 130, a hub with insertion needles 140 (the hub having a finger grip member that allows the hub to be gripped as it is disengaged from the base), a sensor transmitter 150 and an infusion catheter 160.

[0042] Embodiments of this apparatus include those that comprise a subcutaneous sensor and a drug infusion catheter into a single housing, but allows them to be inserted into the skin so that they are spatially separated and/or are disposed in vivo a predetermined 3-D configuration. This separation and/or configuration is designed to diminish interference effects that interfering species in an infusate might have on the sensor itself. In addition, this configuration also may reduce sensor responses to local physiological (or metabolic) effects caused by the infusate. In some embodiments of the invention, the sensor and catheter are inserted into the subcutaneous tissue at a fixed distance apart, for example one where the site of infusion is at least 3, 4, 5, 6, or 7 millimeters from the sensor electrode in an electrochemical sensor. In addition to inhibiting contact between an infusate (e.g. one containing a compound that may interfere with sensor performance) and a sensor electrode, having two separate sites also improves the stability of the device placement in subcutaneous tissue, for example by inhibiting its dislodging from the skin.

[0043] In certain embodiments of the invention, an optimum depth for each of the infusion site and the sensor are independently selected and the configuration of the elements arranged accordingly. For example one embodiment of the apparatus includes an arrangement of elements designed to dispose the infu- sion site in a superficial subcutaneous layer, while disposing the sensor electrode deeper in a layer of the dermis. In particular, the skin includes three distinct layers, a top layer called the epidermis, a middle layer called the dermis and a bottom layer called the subcutaneous layer. The epidermis is about 60 to 120 pm (microns) thick and comprises a number of distinct layers including: a 10 to 20 pm outer layer, called the stratum comeum, followed by the Stratum lu-cidum and stratum granulosum, stratum spinosum and stratum germinativum (also called "stratum basale"). The stratum comeum contains cells filled with bundles of cross-linked keratin and keratohyalin surrounded by an extracellular matrix of lipids. The inner layers are collectively referred to as the viable epidermis and have a total thickness in the range of about 50 to 100 pm. In certain embodiments of the invention, the apparatus is designed to have a configuration that results in the infusion site and/or the sensor being located in one of these layers.

[0044] At the bottom of the epidermis is the basement membrane, which attaches the epidermis firmly, though not rigidly, to the layer below, i.e. the dermis. The dermis is much thicker than the epidermis, having a thickness in the range from about 2,000 to 3,000 pm. The dermal layer generally consists of a dense bed of connective tissue, including collagen fibers, and interstitial fluid dispersed throughout these fibers. The dermis is structurally divided into two areas: a superficial area adjacent to the epidermis, called the papillary region, and a deep thicker area known as the reticular region. The papillary region is composed of loose areolar connective tissue. It is named for its fingerlike projections called papillae, that extend toward the epidermis. The reticular region lies deep in the papillary region and is usually much thicker. It is composed of dense irregular connective tissue, and receives its name from the dense concentration of collagenous, elastic, and reticular fibers that weave throughout it. These protein fibers give the dermis its properties of strength, extensibility, and elasticity. In certain embodiments of the invention, the apparatus is designed to have a configuration that results in the infusion site and/or the sensor being located in one of these layers or areas.

[0045] One exemplary embodiment of an apparatus of the invention is shown in FIG. 4. In this embodiment, the sensor and sensor connector are built toward one edge of the assembly, while the cannula is positioned toward the center; both are at a 90“angle to the skin surface. For insertion, a hub with two needles attached is engaged with the assembly (see, e.g. FIG. 4A). The set is then inserted into the subcutaneous tissue, either manually or with an automatic insertion device. The hub with needles is then removed and discarded (see, e.g. FIG. 4B). The infusion catheter can then be the attached and the sensor is plugged into a cable or transmitter (see, e.g. FIG. 4C and 4D). Alternative embodiments can include for example variations where: an infusion cannula(e) is made from a rigid material, such as stainless steel, that would not require a separate insertion needle; variations where two or more infusion cannulae can be used to further reduce any interference or localized tissue effects (See, e.g. FIG. 4E); variations where a needle and cannula(e) are built into the set at an angle. In other embodiments, the sensor and infusion components of the set are designed in a modular fashion modular so that either one can be removed and replaced independently of the other.

[0046] Embodiments of the invention include apparatuses designed to inhib-it/avoid sensor interference caused by an interfering substance that is present in an infusate. One method of using the apparatus embodying the invention is a method for inhibiting interference of an electrochemical sensor that monitors a body characteristic of a patient, wherein the interference is caused by a inter-ferant present in an infusate (e.g. a phenolic preservative) that is infused by an apparatus for supplying a fluid to a body of a patient, the method comprising supplying a fluid to a body of a patient using an apparatus comprising a base adapted to secure the apparatus to the skin of a patient, a first piercing member coupled to and extending from the base, wherein the first piercing member comprises at least one cannula for infusing a fluid to an infusion site, a second piercing member coupled to and extending from the base and including the electrochemical sensor having a sensor electrode for determining at least one body characteristic of the patient at a sensor placement site, wherein the first and second piercing members are coupled to the base in an orientation such that when the first and second piercing members are inserted into a patient, a first perforation channel made by the first piercing member is not in operable contact with a second perforation channel made by the second piercing member such that a fluid infused to the infusion site cannot flow through the first perforation channel or the second perforation channel to the sensor, so that interference is inhibited.

[0047] Embodiments of the invention further include those having additional and/or multiple methodological functions. For example, in addition to inhibiting interference, certain embodiments of the invention are further designed to stabilize the apparatus by securing it to the patient. One such embodiment of the invention uses an apparatus where the first and second piercing members are coupled to the base in an orientation so that when the cannula and the sensor electrode are disposed in a patient, they function to anchor the apparatus to the skin of the patient. Embodiments of the invention also include those designed for use with certain sensor embodiments. In one such embodiment, the method is designed to inhibit interference observed in a sensor having a plurality of layers, wherein at least one of the layers comprises a base substrate on which the electrode is disposed, the base substrate including a geometric feature selected to increase the surface area of an electrochemically reactive surface on the electrode disposed thereon such that surface area to volume ratio of the electrochemically reactive surface area of the electrode disposed on the geometric feature is greater than surface area-to-volume ratio of the reactive surface of the electrode when disposed on a flat surface, or an analyte sensing layer that detectably alters the electrical current at the electrode in the presence of an analyte, or an adhesion promoting layer that promotes the adhesion between one or more layers of the sensor, or an analyte modulating layer that modulates the diffusion of a analyte therethrough; or a cover layer that is impermeable to blood glucose, wherein the cover layer includes an aperture.

[0048] Yet another embodiment of the invention is a method of making a dual infusion set apparatus for implantation within a mammal comprising the steps of providing a base layer and then disposing an infusion element (or a constellation of infusion elements) on the base and then further disposing a sensor element (or a constellation of sensor elements) on the base to that the apparatus is made. Typically, the 3-D configuration of these elements is controlled during manufacture so as to precisely control the resulting placement of the elements in vivo. Optionally, the sensor element can be made by forming a conductive layer on the base layer, wherein the conductive layer includes a working electrode; forming an analyte sensing layer on the conductive layer, wherein the analyte sensing layer includes a composition that can alter the electrical current at the working electrode in the conductive layer in the presence of an analyte; optionally forming a protein layer on the analyte sensing layer; forming an adhesion promoting layer on the analyte sensing layer or the optional protein layer; forming an analyte modulating layer disposed on the adhesion promoting layer, wherein the analyte modulating layer includes a composition that modulates the diffusion of the analyte therethrough and then forming a cover layer disposed on at least a portion of the analyte modulating layer, wherein the cover layer further includes an aperture over at least a portion of the analyte modulating layer.

B. DIAGRAMMATIC ILLUSTRATION OF TYPICAL SENSOR CONFIGURATIONS

[0049] FIG. 2 illustrates a cross-section of a typical sensor structure that can be used with embodiments of the present invention. The sensor is formed from a plurality of components that are typically in the form of layers of various conductive and non-conductive constituents disposed on each other according to a method of the invention to produce a sensor structure. The components of the sensor are typically characterized herein as layers because, for example, it allows for a facile characterization of the sensor structure shown in FIG. 2. Artisans will understand however, that in certain embodiments of the invention, the sensor constituents are combined such that multiple constituents form one or more heterogeneous layers. In this context, those of skill in the art understand that the ordering of the layered constituents can be altered in various embodiments of the invention.

[0050] The embodiment shown in FIG. 2 includes a base layer 102 to support the sensor. The base layer 102 can be made of a material such as a metal and/or a ceramic and/or a polymeric substrate, which may be self-supporting or further supported by another material as is known in the art. Embodiments of the invention include a conductive layer 104 which is disposed on and/or combined with the base layer 102. In certain embodiments, the base layer 102 and/or the conductive layer 104 can be constructed to produce electrodes having a configuration where the electrochemically reactive surface area of an electrode is disposed on the geometric feature so that the electrochemically reactive surface area is greater than if it was disposed on a flat surface.

[0051] Typically the conductive layer 104 comprises one or more electrodes. An operating sensor typically includes a plurality of electrodes such as a working electrode, a counter electrode and a reference electrode. Other embodiments may also include an electrode that performs multiple functions, for example one that functions as both as a reference and a counter electrode. Still other embodiments may utilize a separate reference element not formed on the sensor. Typically these electrodes are electrically isolated from each other, while situated in close proximity to one another.

[0052] As discussed in detail below, the base layer 102 and/or conductive layer 104 can be generated using many known techniques and materials. In certain embodiments of the invention, the electrical circuit of the sensor is defined by etching the disposed conductive layer 104 into a desired pattern of conductive paths. A typical electrical circuit for the sensor comprises two or more adjacent conductive paths with regions at a proximal end to form contact pads and regions at a distal end to form sensor electrodes. An electrically insulating cover layer 106 such as a polymer coating is optionally disposed on portions of the sensor. Acceptable polymer coatings for use as the insulating protective cover layer 106 can include, but are not limited to, non-toxic biocompatible polymers such as silicone compounds, polyimides, biocompatible solder masks, epoxy acrylate copolymers, or the like. In the sensors of the present invention, one or more exposed regions or apertures 108 can be made through the cover layer 106 to open the conductive layer 104 to the external environment and to, for example, allow an analyte such as glucose to permeate the layers of the sensor and be sensed by the sensing elements. Apertures 108 can be formed by a number of techniques, including laser ablation, tape masking, chemical milling or etching or photolithographic development or the like. In certain embodiments of the invention, during manufacture, a secondary photoresist can also be applied to the protective layer 106 to define the regions of the protective layer to be removed to form the aperture(s) 108. The exposed electrodes and/or contact pads can also undergo secondary processing (e.g. through the apertures 108), such as additional plating processing, to prepare the surfaces and/or strengthen the conductive regions.

[0053] In the sensor configuration shown in FIG. 2, an analyte sensing layer 110 (which is typically a sensor chemistry layer, meaning that materials in this layer undergo a chemical reaction to produce a signal that can be sensed by the conductive layer) is disposed on one or more of the exposed electrodes of the conductive layer 104. Typically, the sensor chemistry layer 110 is an enzyme layer. Most typically, the sensor chemistry layer 110 comprises an enzyme capable of producing and/or utilizing oxygen and/or hydrogen peroxide, for example the enzyme glucose oxidase. Optionally the enzyme in the sensor chemistry layer is combined with a second carrier protein such as human serum albumin, bovine serum albumin or the like. In an illustrative embodiment, an enzyme such as glucose oxidase in the sensor chemistry layer 110 reacts with glucose to produce hydrogen peroxide, a compound which then modulates a current at an electrode. As this modulation of current depends on the concentration of hydrogen peroxide, and the concentration of hydrogen peroxide correlates to the concentration of glucose, the concentration of glucose can be determined by monitoring this modulation in the current. In a specific embodiment of the invention, the hydrogen peroxide is oxidized at a working electrode which is an anode (also termed herein the anodic working electrode), with the result ing current being proportional to the hydrogen peroxide concentration. Such modulations in the current caused by changing hydrogen peroxide concentrations can by monitored by any one of a variety of sensor detector apparatuses such as a universal sensor amperometric biosensor detector or one of the other variety of similar devices known in the art such as glucose monitoring devices produced by Medtronic MiniMed.

[0054] The analyte sensing layer 110 can be applied over portions of the conductive layer or over the entire region of the conductive layer. Typically the analyte sensing layer 110 is disposed on the working electrode which can be the anode or the cathode. Optionally, the analyte sensing layer 110 is also disposed on a counter and/or reference electrode. While the analyte sensing layer 110 can be up to about 1000 microns (pm) in thickness, typically the analyte sensing layer is relatively thin as compared to those found in sensors previously described in the art, and is for example, typically less than 1, 0.5, 0.25 or 0.1 microns in thickness. As discussed in detail below, some methods for generating a thin analyte sensing layer 110 include spin coating processes, dip and dry processes, low shear spraying processes, ink-jet printing processes, silk screen processes and the like. Most typically the thin analyte sensing layer 110 is applied using a spin coating process.

[0055] Typically, the analyte sensing layer 110 is coated with one or more additional layers. Optionally, the one or more additional layers includes a protein layer 116 disposed upon the analyte sensing layer 110. Typically, the protein layer 116 comprises a protein such as albumin or the like. Typically, the protein layer 116 comprises human serum albumin. In some embodiments of the invention, an additional layer includes an analyte modulating layer 112 that is disposed above the analyte sensing layer 110 to regulate analyte contact with the analyte sensing layer 110. For example, the analyte modulating membrane layer 112 can comprise a glucose limiting membrane, which regulates the amount of glucose that contacts an enzyme such as glucose oxidase that is present in the analyte sensing layer. Such glucose limiting membranes can be made from a wide variety of materials known to be suitable for such purposes, e.g., silicone compounds such as polydimethyl siloxanes, polyurethanes, polyurea cellulose acetates, Nation, polyester sulfonic acids (e.g. Kodak AQ), hydrogels or any other suitable hydrophilic membranes known to those skilled in the art. Typically, the analyte modulating layer comprises a hydrophilic comb-copolymer having a central chain and a plurality of side chains coupled to the central chain, wherein at least one side chain comprises a silicone moiety.

[0056] In typical embodiments of the invention, an adhesion promoter layer 114 is disposed between the analyte modulating layer 112 and the analyte sensing layer 110 as shown in FIG. 2 in order to facilitate their contact and/or adhesion. In a specific embodiment of the invention, an adhesion promoter layer 114 is disposed between the analyte modulating layer 112 and the protein layer 116 as shown in FIG. 2 in order to facilitate their contact and/or adhesion. The adhesion promoter layer 114 can be made from any one of a wide variety of materials known in the art to facilitate the bonding between such layers. Typically, the adhesion promoter layer 114 comprises a silane compound. In alternative embodiments, protein or like molecules in the analyte sensing layer 110 can be sufficiently crosslinked or otherwise prepared to allow the analyte modulating membrane layer 112 to be disposed in direct contact with the analyte sensing layer 110 in the absence of an adhesion promoter layer 114.

C. TYPICAL ANALYTE SENSOR CONSTITUENTS

[0057] The following disclosure provides examples of typical ele-ments/constituents used in the sensors of the invention. While these elements can be described as discreet units (e.g. layers), those of skill in the art understand that sensors can be designed to contain elements having a combination of some or all of the material properties and/or functions of the ele-ments/constituents discussed below (e.g. an element that serves both as a supporting base constituent and/or a conductive constituent and/or a matrix for the analyte sensing constituent and which further functions as an electrode in the sensor).

BASE CONSTITUENT

[0058] Sensors of the invention typically include a base constituent (see, e.g. element 102 in Figure 2). The term "base constituent" is used herein according to art accepted terminology and refers to the constituent in the apparatus that typically provides a supporting matrix for the plurality of constituents that are stacked on top of one another and comprise the functioning sensor. In one form, the base constituent comprises a thin film sheet of insulative (e.g. electrically insulative and/or water impermeable) material. This base constituent can be made of a wide variety of materials having desirable qualities such as water impermeability and hermeticity. Some materials include metallic ceramic and polymeric substrates or the like. In certain embodiments, the base constituent and/or the conductive constituent can be constructed to produce electrodes having a configuration where the electrochemically reactive surface area of an electrode is disposed on the geometric feature so that the electrochemically reactive surface area is greater than if it was disposed on a flat surface.

[0059] The base constituent may be self-supporting or further supported by another material as is known in the art. In one embodiment of the sensor configuration shown in Figure 2, the base constituent 102 comprises a ceramic. In an illustrative embodiment, the ceramic base comprises a composition that is predominantly Al203 (e.g. 96%). The use of alumina as an insulating base constituent for use with implantable devices is disclosed in U.S. Pat. Nos. 4,940,858, 4,678,868 and 6,472,122..

[0060] The base constituents of the invention can further include other elements known in the art, for example hermetical vias (see, e.g. WO 03/023388). Depending upon the specific sensor design, the base constituent can be relatively thick constituent (e.g. thicker than 25 microns). Alternatively, one can utilize a nonconductive ceramic, such as alumina, in thin constituents, e.g., less than about 25 microns.

[0061] Arrangements disclosed herein provide individual elements and sensors which exhibit a combination of the independent advantages found in each of the two sensor classes disclosed above. For example a first embodiment of the invention immobilizes an enzyme onto a thick (1-1,000 micron), porous substrate which functions as an electrode in the sensor. In this context, the porous electrode is designed to exhibit an increased surface area, for example by constructing it from a lattice of equal-sized adjoining spheres. In one illustrative embodiment, glucose oxidase is immobilized on a thick (1-1,000 micron), porous metallic substrate that is manufactured from a lattice of equal-sized adjoining spheres and which function as a hydrogen peroxide-consuming electrode.

[0062] In another arrangement disclosed herein the hydrogel typically utilized in a variety of analyte sensors is replaced with an essentially rigid, non-swelling porous enzyme-polymer matrix. In this arrangement bio-sensing enzymes can be stably immobilized via covalent bonding to a rigid, macroporous polymer that has optionally been molded into a specified shape. In this context, molded continuous rods of macroporous polymers have been developed for use as chromatographic separation media (see, e.g. US 5,453,185 and WO 93/07945). Suitable polymers are essentially incompressible and do not change their overall size in response to changes in their solvating environment. Moreover, adjustments to the polymerization conditions can be used to control the morphology of the pores. Hence, highly porous (50-70%) polymers can be created that possess significant volume fractions of pores in the ranges of 1-100 nm and 100-3,000 nm (i.e. 20% and 80%, respectively). Polymers with this type of pore structure possess a very high specific surface area (i.e. 185 m2/g), and are expected to allow for high enzyme immobilization densities (1-100 mg/ml_).

[0063] Various methods and compositions for making and using the above-noted porous matrices as well as analyte sensors which incorporate such matrices are further described herein.

CONDUCTIVE CONSTITUENT

[0064] The electrochemical sensors that may be used with embodiments of the invention typically include a conductive constituent disposed upon the base constituent that includes at least one electrode for contacting an analyte or its byproduct (e.g. oxygen and/or hydrogen peroxide) to be assayed (see, e.g. element 104 in Figure 2). The term "conductive constituent" is used herein according to art accepted terminology and refers to electrically conductive sensor elements such as electrodes which are capable of measuring and a detectable signal and conducting this to a detection apparatus. An illustrative example of this is a conductive constituent that can measure an increase or decrease in current in response to exposure to a stimuli such as the change in the concentration of an analyte or its byproduct as compared to a reference electrode that does not experience the change in the concentration of the analyte, a coreactant (e.g. oxygen) used when the analyte interacts with a composition (e.g. the enzyme glucose oxidase) present in analyte sensing constituent 110 or a reaction product of this interaction (e.g. hydrogen peroxide). Illustrative examples of such elements include electrodes which are capable of producing variable detectable signals in the presence of variable concentrations of molecules such as hydrogen peroxide or oxygen. Typically one of these electrodes in the conductive constituent is a working electrode, which can be made from non-corroding metal or carbon. A carbon working electrode may be vitreous or graphitic and can be made from a solid or a paste. A metallic working electrode may be made from platinum group metals, including palladium or gold, or a non-corroding metallically conducting oxide, such as ruthenium dioxide. Alternatively the electrode may comprise a silver/silver chloride electrode composition. The working electrode may be a wire or a thin conducting film applied to a substrate, for example, by coating or printing. Typically, only a portion of the surface of the metallic or carbon conductor is in electrolytic contact with the analyte-containing solution. This portion is called the working surface of the electrode. The remaining surface of the electrode is typically isolated from the solution by an electrically insulating cover constituent 106. Examples of useful materials for generating this protective cover constituent 106 include polymers such as polyimides, polytetrafluoroethylene, polyhexafluoropropylene and silicones such as pol-ysiloxanes.

[0065] In addition to the working electrode, the analyte sensors of the invention typically include a reference electrode or a combined reference and counter electrode (also termed a quasi-reference electrode or a counter/reference electrode). If the sensor does not have a counter/reference electrode then it may include a separate counter electrode, which may be made from the same or different materials as the working electrode. Typical sensors of the present invention have one or more working electrodes and one or more counter, reference, and/or counter/reference electrodes. One exemplary sensor has two, three or four or more working electrodes. These working electrodes in the sensor may be integrally connected or they may be kept separate.

[0066] Typically, for in vivo use the analyte sensors are implanted subcutaneously in the skin of a mammal for direct contact with the body fluids of the mammal, such as blood. Alternatively the sensors can be implanted into other regions within the body of a mammal such as in the intraperotineal space. When multiple working electrodes are used, they may be implanted together or at different positions in the body. The counter, reference, and/or counter/reference electrodes may also be implanted either proximate to the working electrode(s) or at other positions within the body of the mammal.

INTERFERENCE REJECTION CONSTITUENT

[0067] The electrochemical sensors optionally include an interference rejection constituent disposed between the surface of the electrode and the environment to be assayed. In particular, certain sensor embodiments rely on the oxidation and/or reduction of hydrogen peroxide generated by enzymatic reactions on the surface of a working electrode at a constant potential applied. Because am-perometric detection based on direct oxidation of hydrogen peroxide requires a relatively high oxidation potential, sensors employing this detection scheme may suffer interference from oxidizable species that are present in biological flu ids such as ascorbic acid, uric acid and acetaminophen. In this context, the term "interference rejection constituent" is used herein according to art accepted terminology and refers to a coating or membrane in the sensor that functions to inhibit spurious signals generated by such oxidizable species which interfere with the detection of the signal generated by the analyte to be sensed. Examples of interference rejection constituents include one or more layers or coatings of compounds such as hydrophilic polyurethanes, cellulose acetate (including cellulose acetate incorporating agents such as polyethylene glycol), polyether-sulfones, polytetrafluoroethylenes, the perfluoronated ionomer Nation™, poly-phenylenediamine, epoxy and the like. Illustrative discussions of such interference rejection constituents are found for example in Ward et al., Biosensors and Bioelectronics 17 (2002) 181-189 and Choi et al., Analytical Chimica Acta 461 (2002)251-260.

ANALYTE SENSING CONSTITUENT

[0068] The electrochemical sensors may include an analyte sensing constituent disposed on the electrodes of the sensor (see, e.g. element 110 in Figure 2). The term "analyte sensing constituent" is used herein according to art accepted terminology and refers to a constituent comprising a material that is capable of recognizing or reacting with an analyte whose presence is to be detected by the analyte sensor apparatus. Typically this material in the analyte sensing constituent produces a detectable signal after interacting with the analyte to be sensed, typically via the electrodes of the conductive constituent. In this regard the analyte sensing constituent and the electrodes of the conductive constituent work in combination to produce the electrical signal that is read by an apparatus associated with the analyte sensor. Typically, the analyte sensing constituent comprises an enzyme capable of reacting with and/or producing a molecule whose change in concentration can be measured by measuring the change in the current at an electrode of the conductive constituent (e.g. oxygen and/or hydrogen peroxide), for example the enzyme glucose oxidase. An enzyme capable of producing a molecule such as hydrogen peroxide can be disposed on the electrodes according to a number of processes known in the art. The analyte sensing constituent can coat all or a portion of the various electrodes of the sensor. In this context, the analyte sensing constituent may coat the electrodes to an equivalent degree. Alternatively the analyte sensing constituent may coat different electrodes to different degrees, with for example the coated surface of the working electrode being larger than the coated surface of the counter and/or reference electrode.

[0069] Typical sensors utilize an enzyme (e.g. glucose oxidase) that has been combined with a second protein (e.g. albumin) in a fixed ratio (e.g. one that is typically optimized for glucose oxidase stabilizing properties) and then applied on the surface of an electrode to form a thin enzyme constituent. In a typical embodiment, the analyte sensing constituent comprises a GOx and HSA mixture. In a typical embodiment of an analyte sensing constituent having GOx, the GOx reacts with glucose present in the sensing environment (e.g. the body of a mammal) and generates hydrogen peroxide according to the reaction shown in Figure 1, wherein the hydrogen peroxide so generated is anodically detected at the working electrode in the conductive constituent. As discussed for example in published U.S. Patent Application US 2004/0074785 extremely thin sensor chemistry constituents are typical and can be applied to the surface of the electrode matrix by processes known in the art such as spin coating. In an illustrative embodiment, a glucose oxidase/albumin is prepared in a physiological solution (e.g., phosphate buffered saline at neutral pH) with the albumin being present in a range of about .5%-10% by weight. Optionally the stabilized glucose oxidase constituent that is formed on the analyte sensing constituent is very thin as compared to those previously described in the art, for example less than 2, 1, 0.5, 0.25 or 0.1 microns in thickness. One illustrative arrangement utilizes a stabilized glucose oxidase constituent for coating the surface of an electrode wherein the glucose oxidase is mixed with a carrier protein in a fixed ratio within the constituent, and the glucose oxidase and the carrier protein are distributed in a substantially uniform manner throughout the constituent. Typically the constituent is less than 2 microns in thickness. For purposes of clarity, it should be noted that this may not apply to certain arrangements where the analyte sensing constituent is disposed on a porous electrode. For example, in a porous electrode that is 100 microns thick, with 3 micron size pores that are filled with GOx, an enzyme layer can be greater 2 microns.

[0070] Surprisingly, sensors having these extremely thin analyte sensing constituents have material properties that exceed those of sensors having thicker coatings including enhanced longevity, linearity, regularity as well as improved signal to noise ratios. While not being bound by a specific scientific theory, it is believed that sensors having extremely thin analyte sensing constituents have surprisingly enhanced characteristics as compared to those of thicker constituents because in thicker enzyme constituents only a fraction of the reactive enzyme within the constituent is able to access the analyte to be sensed. In sensors utilizing glucose oxidase, the thick coatings produced by electrodeposition may hinder the ability of hydrogen peroxide generated at the reactive interface of a thick enzyme constituent to contact the sensor surface and thereby generate a signal.

[0071] As noted above, the enzyme and the second protein are typically treated to form a crosslinked matrix (e.g. by adding a cross-linking agent to the protein mixture). As is known in the art, crosslinking conditions may be manipulated to modulate factors such as the retained biological activity of the enzyme, its mechanical and/or operational stability. Illustrative crosslinking procedures are described in U.S. Patent Application Serial Number 10/335,506 and PCT publication WO 03/035891. For example, an amine cross-linking reagent, such as, but not limited to, glutaraldehyde, can be added to the protein mixture. The addition of a cross-linking reagent to the protein mixture creates a protein paste. The concentration of the cross-linking reagent to be added may vary according to the concentration of the protein mixture. While glutaraldehyde is an illustrative crosslinking reagent, other cross-linking reagents may also be used or may be used in place of glutaraldehyde, including, but not limited to, an amine reactive, homofunctional, cross-linking reagent such as Disuccinimidyl Suberate (DSS). Another example is 1-Ethyl-3 (3-Dimethylaminopropyl) Carbodiimide (EDC), which is a zero-length cross-linker. EDC forms an amide bond between carbox ylic acid and amine groups. Other suitable cross-linkers also may be used, as will be evident to those skilled in the art.

[0072] The GOx and/or carrier protein concentration may vary for different embodiments of the invention. For example, the GOx concentration may be within the range of approximately 50 mg/ml (approximately 10,000 U/ml) to approximately 700 mg/ml (approximately 150,000 U/ml). Typically the GOx concentration is about 115 mg/ml (approximately 22,000 U/ml). In such embodiments, the HSA concentration may vary between about 0.5%-30% (w/v), depending on the GOx concentration. Typically the HSA concentration is about 1-10% w/v, and most typically is about 5% w/v. In alternative arrangements, collagen or BSA or other structural proteins used in these contexts can be used instead of or in addition to HSA. Although GOx is discussed as an illustrative enzyme in the analyte sensing constituent, other proteins and/or enzymes may also be used or may be used in place of GOx, including, but not limited to glucose dehydrogenase or hexokinase, hexose oxidase, lactate oxidase, and the like. Other proteins and/or enzymes may also be used, as will be evident to those skilled in the art. Moreover, although HSA is employed in the example embodiment, other structural proteins, such as BSA, collagens or the like, could be used instead of or in addition to HSA.

[0073] For embodiments employing enzymes other than GOx, concentrations other than those discussed herein may be utilized. For example, depending on the enzyme employed, concentrations ranging from approximately 10% weight per weight to 70% weight per weight may be suitable. The concentration may be varied not only depending on the particular enzyme being employed, but also depending on the desired properties of the resulting protein matrix. For example, a certain concentration may be utilized if the protein matrix is to be used in a diagnostic capacity while a different concentration may be utilized if certain structural properties are desired. Those skilled in the art will understand that the concentration utilized may be varied through experimentation to determine which concentration (and of which enzyme or protein) may yield the desired result.

[0074] As noted above the analyte sensing constituent may include a composition (e.g. glucose oxidase) capable of producing a signal (e.g. a change in oxygen and/or hydrogen peroxide concentrations) that can be sensed by the electrically conductive elements (e.g. electrodes which sense changes in oxygen and/or hydrogen peroxide concentrations). However, other useful analyte sensing constituents can be formed from any composition that is capable of producing a detectable signal that can be sensed by the electrically conductive elements after interacting with a target analyte whose presence is to be detected. The composition may comprises an enzyme that modulates hydrogen peroxide concentrations upon reaction with an analyte to be sensed. Alternatively, the composition comprises an enzyme that modulates oxygen concentrations upon reaction with an analyte to be sensed. In this context, a wide variety of enzymes that either use or produce hydrogen peroxide and/or oxygen in a reaction with a physiological analyte are known in the art and these enzymes can be readily incorporated into the analyte sensing constituent composition. A variety of other enzymes known in the art can produce and/or utilize compounds whose modulation can be detected by electrically conductive elements such as the electrodes that are incorporated into the sensor designs described herein. Such enzymes include for example, enzymes specifically described in Table 1, pages 15-29 and/or Table 18, pages 111-112 of Protein Immobilization: Fundamentals and Applications (Bioprocess Technology, Vol 14) by Richard F. Taylor (Editor) Publisher: Marcel Dekker; (January 7, 1991).

[0075] Other useful analyte sensing constituents can be formed to include antibodies whose interaction with a target analyte is capable of producing a detectable signal that can be sensed by the electrically conductive elements after interacting with the target analyte whose presence is to be detected. For example U.S. Patent No. 5,427,912 describes an antibody-based apparatus for electro-chemically determining the concentration of an analyte in a sample. In this device, a mixture is formed which includes the sample to be tested, an enzyme-acceptor polypeptide, an enzyme-donor polypeptide linked to an analyte analog (enzyme-donor polypeptide conjugate), a labeled substrate, and an antibody specific for the analyte to be measured. The analyte and the enzyme-donor polypeptide conjugate competitively bind to the antibody. When the enzyme-donor polypeptide conjugate is not bound to antibody, it will spontaneously combine with the enzyme acceptor polypeptide to form an active enzyme complex. The active enzyme then hydrolyzes the labeled substrate, resulting in the generation of an electroactive label, which can then be oxidized at the surface of an electrode. A current resulting from the oxidation of the electroactive compound can be measured and correlated to the concentration of the analyte in the sample. U.S. Patent No. 5,149,630 describes an electrochemical specific binding assay of a ligand (e.g., antigen, hapten or antibody) wherein at least one of the components is enzyme-labelled, and which includes the step of determining the extent to which the transfer of electrons between the enzyme substrate and an electrode, associated with the substrate reaction, is perturbed by complex formation or by displacement of any ligand complex relative to unbound enzyme-labelled component. The electron transfer is aided by electron-transfer mediators which can accept electrons from the enzyme and donate them to the electrode or vice versa (e.g. ferrocene) or by electron-transfer promoters which retain the enzyme in close proximity with the electrode without themselves taking up a formal charge. U.S. Patent No. 5,147,781 describes an assay for the determination of the enzyme lactate dehydrogenase-5 (LDH5) and to a biosensor for such quantitative determination. The assay is based on the interaction of this enzyme with the substrate lactic acid and nicotine-amine adenine dinucleotide (NAD) to yield pyruvic acid and the reduction product of NAD. Anti-LDH5 antibody is bound to a suitable glassy carbon electrode; this is contacted with the substrate containing LDH5, rinsed, inserted into a NAD solution, connected to an amperometric system, and current changes are measured in the presence of differing concentrations of lactic acid, which are indicative of the quantity of LDH-5. U.S. Patent No. 6,410,251 describes an apparatus and method for detecting or assaying one constituting member in a specific binding pair; for example, the antigen in an antigen/antibody pair, by utilizing specific binding such as binding between an antigen and an antibody, together with redox reaction for detecting a label, wherein an oxygen micro-electrode with a sensing surface area is used. In addition, U.S. Patent No. 4,402,819 describes an antibody- selective potentiometric electrode for the quantitative determination of antibodies (as the analyte) in dilute liquid serum samples employing an insoluble membrane incorporating an antigen having bonded thereto an ion carrier effecting the permeability of preselected cations therein, which permeability is a function of specific antibody concentrations in analysis, and the corresponding method of analysis. For related disclosures, see also U.S. Patent Nos. 6,703,210, 5,981,203, 5,705,399 and 4,894,253.

[0076] In addition to enzymes and antibodies, other exemplary materials for use in the analyte sensing constituents of the sensors disclosed herein include polymers that bind specific types of cells or cell components (e.g. polypeptides, carbohydrates and the like); single-strand DNA; antigens and the like. The detectable signal can be, for example, an optically detectable change, such as a color change or a visible accumulation of the desired analyte (e.g., cells). Sensing elements can also be formed from materials that are essentially non-reactive (i.e., controls). The foregoing alternative sensor elements are beneficially included, for example, in sensors for use in cell-sorting assays and assays for the presence of pathogenic organisms, such as viruses (HIV, hepatitis-C, etc.), bacteria, protozoa and the like.

[0077] Also contemplated are analyte sensors that measure an analyte that is present in the external environment and that can in itself produce a measurable change in current at an electrode. In sensors measuring such analytes, the analyte sensing constituent can be optional.

PROTEIN CONSTITUENT

[0078] The electrochemical sensors suitable for use with embodiments of the invention optionally include a protein constituent disposed between the analyte sensing constituent and the analyte modulating constituent (see, e.g. element 116 in Figure 2). The term "protein constituent" is used herein according to art accepted terminology and refers to constituent containing a carrier protein or the like that is selected for compatibility with the analyte sensing constituent and/or the analyte modulating constituent. The protein constituent comprises an albumin such as human serum albumin. The HSA concentration may vary between about 0.5%-30% (w/v). Typically the HSA concentration is about 1-10% w/v, and most typically is about 5% w/v. In alternative arrangements collagen or BSA or other structural proteins used in these contexts can be used instead of or in addition to HSA. This constituent is typically crosslinked on the analyte sensing constituent according to art accepted protocols.

ADHESION PROMOTING CONSTITUENT

[0079] The electrochemical sensors can include one or more adhesion promoting (AP) constituents (see, e.g. element 114 in Figure 2). The term "adhesion promoting constituent" is used herein according to art accepted terminology and refers to a constituent that includes materials selected for their ability to promote adhesion between adjoining constituents in the sensor. Typically, the adhesion promoting constituent is disposed between the analyte sensing constituent and the analyte modulating constituent. Typically, the adhesion promoting constituent is disposed between the optional protein constituent and the analyte modulating constituent. The adhesion promoter constituent can be made from any one of a wide variety of materials known in the art to facilitate the bonding between such constituents and can be applied by any one of a wide variety of methods known in the art. Typically, the adhesion promoter constituent comprises a silane compound such as y-aminopropyltrimethoxysilane.

[0080] The use of silane coupling reagents, especially those of the formula R'Si(OR)3 in which R' is typically an aliphatic group with a terminal amine and R is a lower alkyl group, to promote adhesion is known in the art (see, e.g. U.S. Patent No. 5,212,050 . For example, chemically modified electrodes in which a silane such as y-aminopropyltriethoxysilane and glutaraldehyde were used in a step-wise process to attach and to co-crosslink bovine serum albumin (BSA) and glucose oxidase (GOx) to the electrode surface are well known in the art (see, e.g. Yao, T. Analytica Chim. Acta 1983, 148, 27-33).

[0081] In certain arrangements the adhesion promoting constituent further comprises one or more compounds that can also be present in an adjacent constituent such as the polydimethyl siloxane (PDMS) compounds that serves to limit the diffusion of analytes such as glucose through the analyte modulating constituent. In illustrative embodiments the formulation comprises 0.5-20% PDMS, typically 5-15% PDMS, and most typically 10% PDMS. The adhesion promoting constituent may include an agent selected for its ability to crosslink a siloxane moiety present in a proximal constituent such as the analyte modulating constituent. In closely related arrangements the adhesion promoting constituent includes an agent selected for its ability to crosslink an amine or carboxyl moiety of a protein present in a proximal constituent such a the analyte sensing constituent and/or the protein constituent.

ANALYTE MODULATING CONSTITUENT

[0082] The electrochemical sensors may include an analyte modulating constituent disposed on the sensor (see, e.g. element 112 in Figure 2). The term "analyte modulating constituent" is used herein according to art accepted terminology and refers to a constituent that typically forms a membrane on the sensor that operates to modulate the diffusion of one or more analytes, such as glucose, through the constituent. In certain embodiments of the invention, the analyte modulating constituent is an analyte-limiting membrane which operates to prevent or restrict the diffusion of one or more analytes, such as glucose, through the constituents. In other arrangements the analyte-modulating constituent operates to facilitate the diffusion of one or more analytes, through the constituents. Optionally such analyte modulating constituents can be formed to prevent or restrict the diffusion of one type of molecule through the constituent (e.g. glucose), while at the same time allowing or even facilitating the diffusion of other types of molecules through the constituent (e.g. 02).

[0083] With respect to glucose sensors, in known enzyme electrodes, glucose and oxygen from blood, as well as some interferants, such as ascorbic acid and uric acid, diffuse through a primary membrane of the sensor. As the glucose, oxygen and interferants reach the analyte sensing constituent, an enzyme, such as glucose oxidase, catalyzes the conversion of glucose to hydrogen peroxide and gluconolactone. The hydrogen peroxide may diffuse back through the analyte modulating constituent, or it may diffuse to an electrode where it can be reacted to form oxygen and a proton to produce a current that is proportional to the glucose concentration. The sensor membrane assembly serves several functions, including selectively allowing the passage of glucose therethrough. In this context, an illustrative analyte modulating constituent is a semi-permeable membrane which permits passage of water, oxygen and at least one selective analyte and which has the ability to absorb water, the membrane having a water soluble, hydrophilic polymer.

[0084] A variety of illustrative analyte modulating compositions are known in the art and are described for example in U.S. Patent Nos. 6,319,540, 5,882,494, 5,786,439 5,777,060, 5,771,868 and 5,391,250. The hydrogels described therein are particularly useful with a variety of implantable devices for which it is advantageous to provide a surrounding water constituent. In some arrangements the analyte modulating composition includes PDMS. In certain arrangements the analyte modulating constituent includes an agent selected for its ability to crosslink a siloxane moiety present in a proximal constituent. In closely related arrangements the adhesion promoting constituent includes an agent selected for its ability to crosslink an amine or carboxyl moiety of a protein present in a proximal constituent.

[0085] As described in detail herein the analyte modulating constituent may comprise a hydrophilic comb-copolymer having a central chain and a plurality of side chains coupled to the central chain, wherein at least one side chain comprises a silicone moiety.

COVER CONSTITUENT

[0086] The electrochemical sensors may include one or more cover constituents which are typically electrically insulating protective constituents (see, e.g. element 106 in Figure 2). Typically, such cover constituents are disposed on at least a portion of the analyte modulating constituent Acceptable polymer coatings for use as the insulating protective cover constituent can include, but are not limited to, non-toxic biocompatible polymers such as silicone compounds, polyimides, biocompatible solder masks, epoxy acrylate copolymers, or the like. Further, these coatings can be photo-imageable to facilitate photolithographic forming of apertures through to the conductive constituent. A typical cover constituent comprises spun on silicone. As is known in the art, this constituent can be a commercially available RTV (room temperature vulcanized) silicone composition. A typical chemistry in this context is polydimethyl siloxane (acetoxy based).

Claims (10)

1. Apparat til levering af et fluidum til en patients legeme og til overvågning af en legemskarakteristik i forbindelse med patienten, hvilket apparat omfatter: en basisdel (100), som er indrettet til at fastgøre apparatet på en patients hud, en første stikkeindretning (130), som er koblet sammen med og rager ud fra basisdelen (100), hvorved den første stikkeindretning (130) er koblet funktionsmæssigt sammen med i det mindste en kanyle til infusion af et fluidum på et infusionssted, en anden stikkeindretning (120), som er koblet sammen med og rager ud fra basisdelen (100) og funktionsmæssigt er koblet sammen med en elektrokemisk føler, som har en følerelektrode (104) til bestemmelse af i det mindste ét legemskarakteristika for patienten på et følerplaceringssted, en infusionssæt-slange (160), som er indrettet til at blive forbundet med kanylen, hvorved den første og den anden stikkeindretning (130, 120) er koblet sammen med basisdelen (100) i en sådan orientering, at n 1. An apparatus for delivering a fluid to the body of a patient and for monitoring a legemskarakteristik associated with the patient, the apparatus comprising: a base portion (100) which is adapted to attach the device on a patient's skin, a first piercing member (130 ), which is coupled to and projecting from the base portion (100), wherein the first piercing member (130) is operatively coupled with at least one needle for infusion of a fluid to an infusion site, a second piercing device (120) which is coupled to and projecting from the base portion (100) and operatively coupled to an electrochemical sensor having a sensing electrode (104) for determining at least one physical characteristics of the patient at a sensor location, by a infusion set tubing (160) which is adapted to be connected to the cannula, wherein the first and the second piercing member (130, 120) is coupled to the base portion (100) in such an orientation that the N r den første og den anden stikkeindretning er koblet funktionsmæssigt sammen med basisdelen og indført i en patient, er den første perforeringskanal, som er fremstillet ved hjælp af den første stikkeindretning, ikke i kontakt med en anden perforeringskanal, som er fremstillet ved hjælp af den anden stikkeindretning, kendetegnet ved, at den første og anden stikkeindretning er anbragt på en hub (140), som kan føres i indgreb med og frakobles basisdelen. r, the first and second piercing is coupled operatively with the base portion and inserted in a patient, the first perforeringskanal, which is produced by means of the first piercing member is not in contact with another perforeringskanal, which is produced by means of the second piercing, characterized in that the first and second piercing member is disposed on a hub (140) which can be engaged with and disconnected from the base portion.
2. Apparat ifølge krav 1, hvorved den første og anden stikkeindretning (130, 120) er koblet til basisdelen (100) med en sådan orientering, at når den første og den anden stikkeindretning (130, 120) er indført i en patient, er infusionsstedet placeret i et lag af epidermis og følerelektroden placeret i et lag af dermis. 2. The apparatus of claim 1, wherein the first and second piercing device (130, 120) is coupled to the base portion (100) with an orientation such that when the first and the second piercing member (130, 120) is inserted into a patient, infusion site located in a layer of the epidermis and the sensing electrode located in a layer of the dermis.
3. Apparat ifølge krav 1, hvorved den første og anden stikkeindretning (130, 120) er koblet sammen med basisdelen (100) med en sådan orientering, at når den første og anden stikkeindretning (130, 120) er indført i en patient, er infusionsstedet og følerelektroden adskilt med i det mindste 7 mm væv. 3. The apparatus of claim 1, wherein the first and second piercing device (130, 120) is coupled to the base portion (100) with an orientation such that when the first and second piercing device (130, 120) is inserted into a patient, infusion site and sensing electrode separated by at least 7 mm tissue.
4. Apparat ifølge krav 1, hvorved hubben (140) omfatter en fingergrebsdel, som tillader hubben (140) at blive grebet, når den frakobles basisdelen (100). 4. The apparatus of claim 1, wherein the hub (140) comprises a fingergrebsdel which allow the hub (140) to be gripped when it is disconnected from the base portion (100).
5. Apparat ifølge krav 1, hvorved den første og anden stikkeindretning (130, 120) er koblet sammen med basisdelen (100) med en sådan orientering, at når kanylen og følerelektroden er placeret i en patient, forankrer kanylen og følerelektroden apparatet til patientens hud, hvorved føleraflæsningerne stabiliseres. 5. The apparatus of claim 1, wherein the first and second piercing device (130, 120) is coupled to the base portion (100) with an orientation such that when the needle and the sensing electrode is placed in a patient, anchors the cannula and the sensing device to the patient's skin wherein the sensor readings to stabilize.
6. Apparat ifølge krav 1, hvorved den første og anden stikkeindretning (130, 120) er metalnåle. 6. The apparatus of claim 1, wherein the first and second piercing device (130, 120) are metal needles.
7. Apparat ifølge krav 1, og som yderligere omfatter en medikamentinfusionspumpe, der er indrettet til at blive forbundet med infusionssætslangen. 7. The apparatus of claim 1, further comprising a medication infusion pump that is adapted to be connected to infusionssætslangen.
8. Apparat ifølge krav 1, hvorved den første stikkeindretning (130) er kortere end den anden stikkeindretning (120). 8. The apparatus of claim 1, wherein the first piercing member (130) is shorter than the second piercing device (120).
9. Apparat ifølge krav 1, hvorved apparatet har en modulform, som tillader kanylen og føleren at blive udskiftet uafhængigt af andre af apparatets komponenter. 9. The apparatus of claim 1, wherein the apparatus has a modular form, which allow the needle and probe to be replaced independently of other components of the apparatus.
10. Apparat ifølge krav 1, hvorved føleren omfatter et antal lag, hvorved i det mindste ét af lagene omfatter: et basissubstrat (102), hvorpå elektroden (104) er placeret, hvilket basissubstrat (102) har et geometrisk træk, som er valgt til at øge overfladearealet for en elektrokemisk aktiv overflade på den derpå placerede elektrode, således at forholdet imellem overfladearealet og volumenet i forbindelse med det elektrokemisk aktive overfladeareal på elektroden (104), der er anbragt på det geometriske træk, er større end forholdet imellem overfladearealet og volumenet i forbindelse med elektrodens (104) aktive overflade, når den er placeret på en flad overflade, et analyt affølingslag (110), som registrerbart ændrer den elektriske strøm ved elektroden under tilstedeværelsen af en analyt, et adhæsionsfremmende lag (114), som fremmer adhæsionen mellem et eller flere af følerens lag, et analyt-moduleringslag (112), som modulerer diffusionen af en analyt derigennem, 10. The apparatus of claim 1, wherein the sensor comprises a plurality of layers, wherein at least one of the layers comprises: a base substrate (102) on which the electrodes (104) are arranged, which base substrate (102) has a geometric feature which is selected to increase the surface area of ​​an electrochemically active surface on the then placed the electrode such that the ratio between the surface area and the volume in connection with the electrochemically active surface area of ​​the electrode (104) disposed on the geometric features is greater than the ratio between the surface area and the volume in connection with the electrode's (104) active surface, when placed on a flat surface, an analyte sensing layer (110) which detectable change the electric current at the electrode in the presence of an analyte, an adhesion promoting layer (114) which promotes the adhesion between one or more of the sensor layer, an analyte modulating layer (112) that modulates the diffusion of the analyte therethrough; eller et dæklag (106), som er uigennemtrængeligt for blodglukose, hvorved dæklaget har en åbning. or a covering layer (106), which is impermeable to blood glucose, wherein the cover layer has an opening.
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